Carbon monoxide (CO) is well-known as a lethal, toxic gas. However, CO is also an important member of the gasotransmitter family of signaling molecules in mammalian systems whose importance is on par with that of NO and H2S. NO was the first identified gaseous small molecule biological messenger in mammals. Nitroglycerin (glyceryl trinitrate) serves as an exogenous source of NO and is the most widely used drug for vasodilation and treatment of heart conditions.
CO also has beneficial therapeutic effects. The endogenous production of CO in a mammalian system occurs through the activity of heme oxygenases (HO-1 and HO-2). These enzymes regulate the catabolism of heme and play an important role in the modulation of a variety of responses, such as stress response and circadian rhythm. Studies have shown that CO has anti-inflammatory, anti-proliferative, and anti-apoptotic effects when the concentrations of CO in carrier gas (air) ranges from 10 to 250 ppm.
CO has been found to play a key beneficial role in various inflammatory and cardiovascular diseases. Among the various inflammatory related disorders, inflammatory bowel disease (IBD), psoriasis, mid-ear infection-induced inflammation, uveitis, and burn- and injury-related inflammation can be effectively treated by CO. For some of the inflammation related conditions, the detailed mechanism may not necessarily be entirely clear. For example, the pathogenesis of IBD is still unclear due to multiple factors involved in the inflammatory processes such as genetic mutations, bacterial infections, and physiological and immunological stress responses. Tumor necrosis factor alpha (TNF-α) plays a central role in the pathogenesis of IBD, as evidenced by the successful treatment of patients with anti-TNF-α antibodies in multiple clinical trials. The anti-inflammatory effects of CO have been reported using cell culture and animal models of sepsis. CO administration or HO-1 overexpression in RAW 264.7 cells inhibits TNF-α expression after treatment with lipopolysaccharide (LPS). In several inflammatory models, CO has been reported to inhibit Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) expression, resulting in attenuation of inflammation. The effective and targeted treatments of IBD are largely limited due to significant systemic side effects. Until now, anti-inflammatory drugs and immunosuppressants are two options used in IBD treatment. There are some mitogen-activated protein kinase (MAPK) inhibitors being developed as treatment options. For other inflammation-related symptoms, the situation is similar. For example, psoriasis has limited effective treatment options, e.g., corticoid hormone and anti-TNFα.
Rheumatoid arthritis and osteoarthritis are two more examples of inflammatory disorders that can be treated with CO. Administration of CO from carbon monoxide releasing molecules (CORMs) in a model of collagen-induced arthritis suppressed the clinical and histopathological manifestations of the disease. The data is consistent with the reduction in the levels of inflammatory cytokines such as interleukins and TNF-α in joint tissue, and showed decreased cellular infiltration, joint inflammation and cartilage destruction.
Besides anti-inflammatory effects, evidence suggests that CO plays a beneficial role in treating cardiovascular disease. Pulmonary arterial hypertension (PAH), one type of pulmonary hypertension, is an incurable disease at this moment, and is described as high blood pressure in the arteries of the lungs. It is driven by an increased expansion of vascular smooth muscle in the pulmonary arterioles and leads to right heart hypertrophy and infarct. Breathing low concentrations of CO gas (e.g., 150 ppm) has been investigated as a treatment to improve pulmonary arterial hypertension and is currently in phase II clinical trials. Preliminary results have shown that after 16 weeks, the pulmonary vascular resistance has decreased 20% compared to the pre-therapy value. The mechanism of action of CO in the treatment of PAH has been reported as involving endothelial derived NO to induce apoptosis of the hyper-proliferative vascular smooth muscle cells.
A key issue in the use of CO as a therapeutic agent is the safe delivery of low doses to the desired site of action. A number of Carbon Monoxide Releasing Molecules (CORMs) have been investigated. Currently available CO delivery systems are metal-containing CORMs that can release CO, especially upon exposure to light and/or water. Manganese-based photo CORMs are representative of these molecules. However, for medicinal applications, especially for systemic administration, overcoming the toxicity of residual metal ions is a key issue.
Boric acid complexes have been investigated for non-photochemical approaches for the delivery of CO in vivo. In the case of CO delivery using UV irradiation, the rate of CO release is generally slow (half-life about 20-fold slower than that of metal-CORMs) and toxicity issues have limited the development of these compounds. Besides organometallic compounds, dialkylaldehydes, oxalates, boroncarboxylates and silacarboxylates are CORMs that are transition-metal free and can release CO under mild conditions. Boroncarboxylates are well known CO releasers and possess good water solubility. Disodium boranocarbonate, for example, has been used in animal models for disease treatment. Silacarboxylic acids (R3SiCOOH) can deliver stoichiometric amounts of CO in the presence a nucleophile. However, toxicity issues and limited ability for chemical transformations make these molecules unsuitable candidates for therapeutic applications.
Some organic reactions release CO as a byproduct. However, the need to use UV light to activate these molecules is a limitation in their application as medicinal agents.
Therefore, there is a need for molecules that generate CO in vivo and in vitro with little or no toxicity and without the need for external stimuli. The present invention addresses this and other needs.